5'-methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene frequently deleted in cancer (~100,000 individuals/year in USA). MTAP loss leads to the accumulation of 5'-methylthioadenosine (MTA) which hinders cell metabolism and binds and partially inhibits protein arginine methyltransferase 5 (PRMT5) activity. Complete inhibition of PRMT5 in MTAP loss cells leads to cell death. MTAP null tumors can be selectively targeted with MTA cooperative PRMT5 inhibitors (MTA:PRMT5i), that inhibit PRMT5 bound to MTA while sparing normal MTAP wild-type tissue. These agents are safe and well tolerated compared to first generation PRMT5 inhibitors. Despite improved safety profile of the MTA:PRMT5...

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5'-methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene frequently deleted in cancer (~100,000 individuals/year in USA). MTAP loss leads to the accumulation of 5'-methylthioadenosine (MTA) which hinders cell metabolism and binds and partially inhibits protein arginine methyltransferase 5 (PRMT5) activity. Complete inhibition of PRMT5 in MTAP loss cells leads to cell death. MTAP null tumors can be selectively targeted with MTA cooperative PRMT5 inhibitors (MTA:PRMT5i), that inhibit PRMT5 bound to MTA while sparing normal MTAP wild-type tissue. These agents are safe and well tolerated compared to first generation PRMT5 inhibitors. Despite improved safety profile of the MTA:PRMT5i, overall responses were modest and short-lived. Therefore, there is a critical need to develop combination strategies for enhanced efficacy and durable responses in patients with MTAP loss. We recently identified increased DNA damage accumulation in MTAP null tumors that can be enhanced with additional PRMT5 inhibition. PRMT5 inhibition further sensitizes cells to Poly ADP-ribose polymerase (PARP) blockade as it disrupts DNA repair machinery, not allowing for repair of the accumulated DNA damage. We believe combining AMG193 (MTA:PRMT5i) with olaparib (PARPi) will be safe, well tolerated, and efficacious in patients with MTAP loss solid tumors. AMG193 has demonstrated clinical safety, and selectivity to PRMT5 blockade in MTAP loss tumor cells at low doses. We therefore propose to combine AMG193 with olaparib as a therapeutic strategy for effective and prolonged response in patients with MTAP loss solid tumors. In this study, we will conduct a first-in-human phase I trial to determine safety, tolerability, and preliminary efficacy of the combination in patients with MTAP loss solid tumors. We will also study the effects of the combination treatment on critical cellular pathways with specific focus on metabolic, transcriptional, DNA repair and immune regulation.

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